Project Summary Alzheimer's disease (AD) is a growing public health issue, affecting 5.4 million people within the United States and an estimated 40 million people worldwide. It is the leading cause of dementia and manifests as progressive decline in memory, cognitive, and motor function. Most therapies in development for AD are based on the amyloid cascade hypothesis, which assumes that amyloid plaques are causal in AD. However, these approaches have so far failed to yield effective treatments to prevent or cure AD. Our lab uses genetics to identify additional genes and pathways that may be contributing to AD in order to identify new drug targets. In this proposal, we focus on the MS4A gene family, which has been associated with AD through genome-wide association studies (GWAS). MS4A genes are specifically expressed within myeloid cells, including microglia, suggesting that these cell types mediate the connection between these genes and AD. Our work has shown that alleles associated with reduced risk for AD are associated with lower levels of expression for MS4A genes. This proposal combines genetic and cell-based approaches to characterize this gene family and investigate its impact on myeloid cells and microglia. We hypothesize that variants within the MS4A GWAS locus affect expression of MS4A genes, that these changes in expression disrupt myeloid cell pathways linked to cholesterol metabolism and phagocytic clearance, and that decreased MS4A gene expression in human stem cell-derived microglia will disrupt microglial function. Our ultimate goal is to use this functional genomics approach to characterize this gene family as a potential drug target for new AD therapies.